Transplantation
Authors: T. E. Starzl
Journal: JAMA (1990)

The three principal struts of transplantation are organ preservation, immunosuppression, and tissue typing.Major pragmatic advances have been made possible by improved static preservation with the University of Wisconsin solution.The safe preservation limits for all organs, but particularly the liver, have been greatly increased since 1987.The most important ingredients of the University of Wisconsin solution are thought to be the impermeants that prevent cell swelling.Two research directions are identifiable in the literature-one, eliminate unneeded constituents of the University of Wisconsin solution, and the other, increase the additives, which already number more than 10. 1 The growth of transplantation during the last decade owes much to cyclosporine.The use of cyclosporine with steroids, to which other agents can be added in more or less elaborate cocktails, made possible the transplantation of cadaveric kidneys, livers, hearts, and other organs with an effectiveness scarcely dreamed of 10 years ago.Yet, the full profile of cyclosporine actions is incomplete. 2 Aside from its immunosuppressive qualities, the spectrum of seemingly unrelated cyclosporine activities is bewildering. 2Nephrotoxicity and hypertension are the best known and principal dose-limiting side effects.Metabolic, cosmetic, and neurotoxic side effects may also occur.Some symptoms may be so subtle that they are not mentioned unless specific inquiries are made.The foregoing side effects of cyclosporine and its desired inhibition of the immune system had not been thought to be interrelated by a common mechanism.This has been changed by clinical observations with another immunosuppressive agent called FK 506 (Fujisawa Corporation, Osaka, Japan), which has a totally different structure than cyclosporine.FK 506 is a macrolide obtained from cultures of Streptomyces tsukubaensis.Like cyclosporine, it inhibits the activation of T lymphocytes, in part by depressing the production and expression of multiple cytokines of which interleukin 2 and interferon gamma have been the most extensively studied. 3The in vivo immunosuppressive qualities of FK 506 have been studied in mice, rats, dogs, monkeys, baboons, and humans. 4To date, there has been only one investigational new drug trial for FK 506, and this has taken place at the University of Pittsburgh.However, multicenter trials are scheduled to begin in the spring of 1990 in Europe and in approximately one dozen American centers.So far, investigational new drug applications have not been developed for indications other than in transplantation.Extensive clinical trials with FK 506 were begun in February 1989, 5,6 first, for the rescue of patients who had intractable liver allograft rejection or toxic reactions under immunosuppression, which included cyclosporine, 5 and subsequently as primary therapy.By February 1, 1990, 36 kidneys, 151 livers, and 14 hearts, lungs, or heart-lung grafts had been transplanted with an immunosuppression regimen of FK 506 and low-dose steroids.All of the thoracic organ recipients and more than 90% of the liver recipients are alive.The kidney recipients, who represented an unusually complex and difficult collection of cases, have a graft survival rate of 80%, with a patient mortality rate of 3%. 7Overall, the low mortality, high graft survival, good graft function rates, and relative nondependence on steroids reflect a large and safe therapeutic window for FK 506.